Hepatocellular carcinoma (HCC) is the sixth most common solid tumor worldwide, with more than half occurring in China (Parkin et al., DM. Int J Cancer. 2006; 118(12):3030-3044). HCC is difficult to diagnose, in particular in early stages of the disease. Because of its poor prognosis, hepatocellular carcinoma is the third leading cause of cancer-related death. (Parkin et al., 2002. CA Cancer J Clin. 2005; 55(2): 74-108). Because of its poor prognosis, it is the third leading cause of cancer-related death (2). Due to such poor prognosis, by the time a subject is diagnosed with HCC the disease has progresses to such an extent that current therapies are largely ineffective. Only a minority of patients with hepatocellular carcinoma are candidates for potentially curative treatments of resection, transplantation, or ablation.
As current therapies are ineffective for most HCC patients, prevention of HBV and HCV transmission, identification of high-risk populations suit able for screening and chemoprevention have been proposed as alternative strategies (Llovet et al., Lancet. 2003; 362(9399):1907-1917). Alternatively, identification of high-risk populations suitable for screening and chemoprevention have been proposed as alternative strategies (3).
Screening strategies for high-risk populations include alpha fetoprotein measurements and liver imaging. These techniques are costly and are hindered by suboptimal sensitivity and specificity. To this end, identification of molecular markers associated with an increased risk of hepatocellular carcinoma would better define populations at highest risk for hepatocellular carcinoma and can additionally define important therapeutic targets for prevention and treatment.
Transformation to HCC commonly occurs in the setting of underlying chronic liver disease (1). HCC commonly arises in the setting of hepatic cirrhosis (Thomas et al., J Clin Oncol. 2005; 23(13): 2892-2899) and chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most important causes of cirrhosis and hepatocellular carcinoma. (IARC. Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol 59. Lyon, France: International Agency for Research on Cancer; 2004).
EGF, first isolated in 1962 (4), has many biological functions. It stimulates proliferation and differentiation of epidermal and epithelial tissues (5, 6). EGF is a known mitogen for adult (7) and fetal hepatocytes (8) grown in culture, and its expression is up-regulated during liver regeneration (9). Mounting evidence supports a role for EGF in malignant transformation and tumor progression (10). EGF enhances in vitro growth of human epithelial and mesenchymal-derived tumors (11). Over-expression of a secreted human EGF fusion protein (IgEGF) in fibroblasts enhances their transformation to fibrosarcomas (12). Transgenic mice with liver-specific over-expression of IgEGF develop HCC (13). Gene expression profiles comparing normal liver tissue to liver tumors in these mice suggest a role for an autocrine mechanism during EGF-induced hepatocarcinogenesis (14).